Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
  • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
  • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/04—Macromolecular materials
  • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds

Definitions

• the invention relates to a beta-amino acid ester, in particular an oligomeric or polymeric beta-amino acid ester, a process for its preparation and the use of this compound as a curing agent for the production of polyurethane ureas or polyureas, in particular for adhesion barriers and tissue adhesives.
• Adhesions are one of the most common complications after abdominal and pelvic surgery. Adhesions are fibrous ligaments that generally develop within the first seven days after surgery as part of the healing process. As a result, tissues and organs that are normally separated from each other grow together, resulting in a variety of complications such as hypertension. chronic pain, infertility or a life-threatening intestinal obstruction may occur. To avoid such complications, products have been developed in recent years that can reduce the formation of adhesions. The success has been limited so far.
• Adhesion barriers consist of an inert or absorbable material that is applied to the appropriate organs.
• materials such as polysaccharides ( US 4886787 . US 5,356,883 ), Hyaluronic acid ( US 4,141,973 . US 5,246,698 ), Alginates ( US 5,266,326 ), Chitin ( US 5,093,319 ), Chitosan ( US 4,532,134 .
• membrane-form products such as INTERCEED TM (Johnson & Johnson), SEPRAFILM TM (Genzyme Corp.), and REPEL-CV TM (Life Medical Corp.), which are absorbed within 28 days. Since the barriers are placed on the appropriate organ, but there is a risk of slipping.
• Barriers such as the hyaluronic acid derivatives SEPRACOAT TM (GenzymeCorp.) And LUBRICOAT TM (Lifecore Biomedical Inc.), are often applied as a liquid quickly degraded by the body, whereby the barrier effect is limited. In addition, there is a risk of migration, so that the protective effect is eliminated.
• Hydrogels are hydrous polymers whose chains are covalently linked to a three-dimensional network. In water, they swell quickly and under a strong volume increase. Due to their high water content hydrogels are in principle of interest as adhesion barriers.
• hydrophilic polyethylene glycol-based systems US 2005/266086 . DE 699 29 278 . US 7,025,990 . US 6,514,534 . US 2003/0077242 ), such as the commercially available SPRAYGEL TM (Confluent Surgical).
• SPRAYGEL TM Confluent Surgical
• redox system-initiated radical polymerisation is frequently mentioned ( WO 00/09087 . US 2003/0077242 . US 2005/0271727 ).
• the redox initiators used include ascorbic acid and peroxides.
• tissue irritations the problem arises of the aqueous consistency of the two reaction partners, which adversely affects adhesion to human or animal organ tissue in this system.
• Isocyanate-capped polymers such as polyester and polyether urethanes are described as postoperative adhesion barriers.
• the isocyanates used are preferably TDI and IPDI (isophorone diisocyanate), the prepolymers containing a content of low molecular weight polyisocyanates such as TDI of 0.05 to 1 meq to effect good adhesion to the fabric. In the presence of biological fluids or in certain tissue types, larger amounts should be present.
• the adhesion occurs inter alia by reaction of the isocyanate with the tissue.
• monomeric isocyanates are known to cause tissue irritation in addition to sensitization and thus allergic reactions.
• the rate of reaction of the prepolymer on the fabric is also greatly slowed using aliphatic isocyanates such as HDI, so that such a system is impractical for clinical use.
• WO 2006/010278 describes the preparation and use of polyurethane prepolymers and polyurethane acrylates as adhesion barrier. These compositions are based on aliphatic isocyanates such as HDI as chain extenders or hardeners are proposed low molecular weight diols, diamines, triols, triamines or oligomers and physiologically active compounds. In addition, the composition contains a catalyst, for which organic zinc, tin, magnesium and iron compounds are used. However, the use of a catalyst generally leads to a strong acceleration of the curing rate of the polymer, which is accompanied by increased heat development. This limits the application to internal organs.
• EP 1 719 530 A1 discloses the use of isocyanate-capped polyester macromers based on aliphatic dicarboxylic acids and dihydroxy components such as polyalkylene oxides or polyethylene glycols.
• Possible isocyanates are aromatic, aliphatic and alicyclic isocyanates.
• Aromatic based isocyanate prepolymers such as TDI (as listed in the examples) have a reported fabric cure time of 1-10 min.
• the use of aromatics-based isocyanates is considered to be critical for use in the body, in which, as with the adhesion barriers, the product is completely degraded, but due to the resulting fission products as critical.
• the WO 2007/067624 discloses a bioabsorbable 2-component system consisting of an isocyanate prepolymer based on glycolide, lactide, e-caprolactone, p-dioxanone, trimethyl carbonate and polyalkylene oxide (eg polyethylene glycols).
• the second component used is a polyamine.
• a gel forms, which can be used as an adhesive or adhesion barrier.
• the prepolymers are very highly viscous, so that application without addition of solvent is likely to be possible.
• solvents including water, alcohols and ketones indicated. Hydroxyl-containing solvents, however, have the problem of rapid reaction with the prepolymer, so that there is a risk of gelation.
• the processing time can be greatly reduced thereby the applicability suffers.
• the use of solvents is generally considered to be critical when used in vivo in most cases due to potential cytotoxicity as well as interaction with the tissue.
• the object underlying the present invention was to provide a hardener with which an adhesion barrier can be provided which forms a flexible film on the organs or the tissue to be protected and good adhesion to the organs to be protected or the like Tissue shows.
• the hardener should enable a high curing speed, which ensures rapid processability.
• the adhesion barrier material should be biocompatible and, if possible, biologically degraded within 6 months or less after application in the human or animal body.
• a beta-amino acid ester obtainable by reacting a di-acrylate of the general formula (I) with a diamine of the general formula (II) wherein R 1 and R 2 are organic radicals without Zerewitinoff-active H atoms and R 3 is an organic radical without Zerewitinoff-active H atom or a hydrogen atom.
• the polyurethane prepolymers cured with the beta-amino acid ester according to the invention are further distinguished by high biocompatibility and are generally degraded within a few weeks after application in the human or animal body.
• the resulting degradation products also have no cell and tissue toxicity, which is also beneficial.
• a NCO-terminated prepolymer cured with the beta-amino acid ester according to the invention does not develop any noteworthy or even tissue-damaging exotherm in the aqueous solution upon curing.
• beta-amino acid ester according to the invention is that its viscosity can be variably adjusted, whereby easy applicability is ensured. At the same time, penetration into deeper tissue layers is avoided.
• the viscosity can be influenced by the choice of the radicals R 1 and R 2 but also to a certain extent by R 3 .
• the viscosity of the chain length of the oligomeric or polymeric beta-amino acid ester formed in the reaction of the compounds of the formulas (I) and (II) can be modified.
• the radicals R 1 , R 2 and R 3 have no Zerewitinoff-active H atoms.
• a Zerewitinoff-active H atom is understood as meaning an acidic H atom or "active" H atom. Such can be determined in a conventional manner by reacting with a corresponding Grignard reagent.
• the amount of Zerewitinoff-active H atoms is typically determined by the methane release released in a reaction of the substance to be tested with methylmagnesium bromide (CH 3 -MgBr) according to the following reaction equation (formula 1): CH 3 -MgBr + ROH ⁇ CH 4 + Mg (OR) Br (1)
• Zerewitinoff active H atoms are typically derived from CH acidic organic groups, -OH, -SH, -NH 2, or -NHR with R as organic residue and -COOH.
• the number of units based in each case on the formulas (I) and (II) can vary over a wide range.
• units derived from formulas (I) and (II) may be used in each case 2 to 20 units may be present in the beta-amino acid ester, wherein the number of units based on the formulas (I) and (II) may be the same or differ by one unit, depending on which of the units of the Amino acid ester is terminated.
• At least one of the amino groups is a primary amino group.
• both amino groups are primary amino groups.
• the reason for this is that the addition of a secondary amino group to the acrylic double bond results in the formation of a tertiary amine which consequently lacks a free hydrogen atom to react with the NCO group of a polyisocyanate.
• a diamine of formula (II) having a secondary amino group the number of reactive centers per unit of formula (II) in the beta-amino acid ester is reduced.
• the at least partial use of amines having a primary and a secondary amino group of the formula (II) may be desired.
• the tertiary amino groups formed in the reaction with compounds of the formula (I) can catalyze the curing of NCO prepolymers.
• the distance of the NCO-reactive groups can be increased, whereby a softer polymer can be obtained.
• R 1 and R 2 are a variety of organic radicals in question.
• R 1 and R 2 are independently selected from polyesterpolyol groups, polyester-polyether-polyol groups and / or polyetherpolyol groups. These groups are characterized by a relatively high polarity, whereby a better tissue adhesion is achieved. In addition, these residues are more readily biodegradable. These building blocks are also flexible, which has an advantageous effect on the softness of the resulting polyurea polymers in the reaction with polyisocyanates. Particular preference is given here to polyester-polyether-polyol groups and / or polyether-polyol groups having an ethylene oxide content of at least 60% by weight.
• radicals R 1 and R 2 in the beta-amino acid ester may vary over wide ranges.
• the radicals R 1 and R 2 independently of one another have a weight average of from 200 to 2000 g / mol, in particular from 300 to 1500 g / mol, preferably from 400 to 1000 g / mol. This is particularly advantageous because it achieves good adhesion to the tissue.
• this will be involved in the implementation Polyisocyanates three-dimensional polymer networks created between the individual polymeric branches have large and bordered by hydrophilic groups of the radicals R 1 and R 2 and the polymer backbone of the polyisocyanates interstices. In these spaces, a larger amount of water can be stored.
• the polyurea polymers formed in the reaction have a high swelling and water absorption capacity and are ideally suited for the formation of hydrogels.
• the radical R 3 can be selected from a multiplicity of compounds. As already stated above, a hydrogen radical is particularly preferred. In addition, R 3 may also be selected from saturated or unsaturated hydrocarbon radicals, in particular from methyl, ethyl or propyl radicals. In this case, short-chain aliphatic radicals having up to 3 carbon atoms are particularly preferred, since they emanate less steric hindrance.
• the beta-amino acid ester according to the invention may have an oligomeric or polymeric structure, which as a rule consists of an alternating arrangement of the structural elements of the formulas (I) and (II).
• the terminal groups are concerned, there are several alternatives to the construction of the beta-amino acid ester.
• the beta-amino acid ester may correspond to the general formula (III) where n is an integer, which is in particular from 1 to 20.
• one primary amino group of the compound of the formula (II) forms one chain end and one acrylic double bond of the diacrylate of the formula (I) the other chain end.
• the beta-amino acid ester may each have two (primary) amines at the respective chain ends or else two acrylic double bonds.
• a mixture of the aforementioned compounds will be established, unless a compound of formula (I) or (II) is used in the appropriate excess.
• the compounds of formulas (I) and (II) will be in an equivalent ratio of about 0.6: 1 to 1.5: 1 used, in particular from about 0.7: 1 to 1.1: 1.
• the ratio is about 0, 8: 1.
• the molecular weight of the beta-amino acid ester according to the invention can be adjusted over a wide range.
• the beta-amino acid ester has a number average molecular weight of 1300 to 25,000, in particular from 3000 to 12,000.
• Another object of the present invention relates to a process for the preparation of a beta-amino acid ester according to the invention in which reacting a diacrylate of the general formula (I) with a diamine of the general formula (II).
• This can be done in the simplest case so that the diamine is initially charged and the diacrylate is added dropwise with stirring.
• the temperature should preferably not rise above 30 ° C. Since the aforementioned reaction is highly exothermic, cooling of the reaction vessel is advisable. After completion of the addition and decayed exotherm, it is then possible to heat to a temperature of, for example, 60.degree. This temperature is preferably maintained for 10 to 14 hours.
• the polyurea systems according to the invention are obtained by mixing the prepolymers A) with the beta-amino acid ester B) according to the invention and optionally the components C), D) and / or E).
• the ratio of free or blocked amino groups to free NCO groups is preferably 1: 1.5, more preferably 1: 1. Water and / or amine are thereby the component B) or C) admixed.
• the isocyanate-functional prepolymers A) can be obtained by reacting polyisocyanates A1) with polyols A2), if appropriate with addition of catalysts and auxiliaries and additives.
• polyisocyanates A1) for example, monomeric aliphatic or cycloaliphatic di- or triisocyanates such as 1,4-butylene diisocyanate (BDI), 1,6-hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), 2,2,4- and / or 2,4 , 4-trimethylhexa-methylene diisocyanate, the isomeric bis (4,4'-isocyanatocyclohexyl) methanes or mixtures thereof any isomer content, 1,4-cyclohexylene diisocyanate, 4-isocyanatomethyl-l, 8-octane diisocyanate (nonane triisocyanate), and alkyl 2,6-diisocyanatohexanoate (lysine diisocyanate) with C1-C8 alkyl groups.
• BDI 1,4-butylene diisocyanate
• HDI 1,6-hex
• polyisocyanates A1) of the abovementioned type with exclusively aliphatically or cycloaliphatically bonded isocyanate groups or mixtures thereof.
• the polyols A2) are polyester polyols and / or polyester-polyether polyols and / or polyether polyols. Particular preference is given to polyester-polyether polyols and / or polyether polyols having an ethylene oxide content of between 60 and 90% by weight.
• the polyols A2) have a number-average molecular weight of 4000 to 8500 g / mol.
• Suitable polyetheresterpolyols preferably by polycondensation of polycarboxylic acids, anhydrides of polycarboxylic acids, and esters of polycarboxylic acids with volatile alcohols, preferably C1 to C6 monools such as methanol, ethanol, propanol or butanol, with molar excess, low molecular weight and / or higher molecular weight Polyol produced; wherein polyols containing ether groups are optionally used in mixtures with other ether group-free polyols.
• mixtures of the higher molecular weight and the low molecular weight polyols can be used for Polyetherestersynthese.
• Such molar excess low molecular weight polyols are polyols having molecular weights of 62 to 299 daltons, having 2 to 12 carbon atoms and hydroxyl functionalities of at least 2, which may further be branched or unbranched and whose hydroxyl groups are primary or secondary. These low molecular weight polyols may also have ether groups.
• Typical representatives are ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 2,3-butanediol, 2-methyl-1,3-propanediol, 1,5-pentanediol, 1,6-hexanediol , 3-methylpentanediol-1,5, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol, cyclohexanediol, diethylene glycol, triethylene glycol and higher homologues, dipropylene glycol, tripropylene glycol and higher homologues, glycerol, 1,1,1 Trimethylolpropane, and hydroxyl terminated oligotetrahydrofurans. Of course, mixtures can be used within this group.
• Molar excess high molecular weight polyols are polyols having molecular weights of 300 to 3000 daltons, which can be obtained by ring-opening polymerization of epoxides, preferably ethylene and / or propylene oxide, as well as acid-catalyzed, ring-opening polymerization of tetrahydrofuran.
• epoxides preferably ethylene and / or propylene oxide
• acid-catalyzed, ring-opening polymerization of tetrahydrofuran For ring-opening polymerization of epoxides, either alkali metal hydroxides or double metal cyanide catalysts can be used.
• As starters for ring-opening Epoxidpolymerisationen all at least bifunctional molecules from the group of amines and the above-mentioned low molecular weight polyols can be used.
• Typical representatives are 1,1,1-trimethylolpropane, glycerol, o-TDA, ethylenediamine, propylene glycol-1,2, etc. as well as water, including mixtures thereof. Of course, mixtures can also be used within the group of excess higher molecular weight polyols.
• the structure of the higher molecular weight polyols as far as it is hydroxyl-terminated polyalkylene oxides of ethylene and / or propylene oxide, can be carried out randomly or in blocks, wherein mixing blocks may be included.
• Polycarboxylic acids are both aliphatic and aromatic carboxylic acids, which may be both cyclic, linear, branched or unbranched and which may have between 4 and 24 carbon atoms.
• Succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, phthalic acid, terephthalic acid, isophthalic acid, trimellitic acid, pyromellitic acid are preferred.
• Particularly preferred are succinic acid, glutaric acid and adipic acid.
• the group of polycarboxylic acids also hydroxycarboxylic acids, or their internal anhydrides, such. Caprolactone, lactic acid, hydroxybutyric acid, ricinoleic acid, etc. Also included are monocarboxylic acids, in particular those which have more than 10 carbon atoms, such as soybean oil fatty acid, palm oil fatty acid and peanut oil fatty acid, wherein their share of the total, the polyetheresterpolyol constituent reaction mixture 10 wt. -% does not exceed and in addition the concomitant minor functionality by the concomitant use of at least trifunctional polyols, it is balanced on the part of the low molecular weight or the high molecular weight polyols.
• monocarboxylic acids in particular those which have more than 10 carbon atoms, such as soybean oil fatty acid, palm oil fatty acid and peanut oil fatty acid, wherein their share of the total, the polyetheresterpolyol constituent reaction mixture 10 wt. -% does not exceed and in addition
• the preparation of the polyetherester polyol is carried out according to the prior art at elevated temperature in the range of 120 to 250 ° C, first under atmospheric pressure, later under application of vacuum from 1 to 100 mbar, preferably, but not necessarily using an esterification or transesterification catalyst, wherein the reaction is completed to such an extent that the acid number decreases to values of 0.05 to 10 mg KOH / g, preferably 0.1 to 3 mg KOH / g and more preferably 0.15 to 2.5 mg KOH / g.
• an inert gas can be used.
• liquid or gaseous entrainers may also be used.
• the reaction water can be discharged using nitrogen as a carrier gas, as well as using an azeotroping agent such as benzene, toluene, xylene, dioxane, etc.
• blends of polyether polyols with polyester polyols in any ratios can be used.
• Polyether polyols are preferably polyalkylene oxide polyethers based on ethylene oxide and optionally propylene oxide.
• polyether polyols are preferably based on di- or higher-functional starter molecules such as dihydric or higher-functional alcohols or amines.
• initiators are water (considered as a diol), ethylene glycol, propylene glycol, butylene glycol, glycerol, TMP, sorbitol, pentaerythritol, triethanolamine, ammonia or ethylenediamine.
• hydroxyl-containing polycarbonates preferably polycarbonatediols, having number-average molecular weights Mn of from 400 to 8000 g / mol, preferably from 600 to 3000 g / mol.
• carbonic acid derivatives such as diphenyl carbonate, dimethyl carbonate or phosgene
• polyols preferably diols.
• diols examples include ethylene glycol, 1,2- and 1,3-propanediol, 1,3- and 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, neopentyl glycol, 1,4-bis-hydroxymethylcyclohexane, 2- Methyl-1,3-propanediol, 2,2,4-trimethylpentanediol-1,3, dipropylene glycol, polypropylene glycols, dibutylene glycol, polybutylene glycols, bisphenol A and lactone-modified diols of the aforementioned type in question.
• the polyisocyanate A1) can be reacted with the polyol A2) at an NCO / OH ratio of preferably 4: 1 to 12: 1, more preferably 8: 1, and then the proportion of unreacted polyisocyanate by means of suitable methods be separated.
• NCO / OH ratio preferably 4: 1 to 12: 1, more preferably 8: 1
• prepolymers having residual monomer contents of less than 1% by weight, preferably less than 0.1 wt .-%, most preferably less than 0.03 wt .-% are obtained.
• stabilizers such as benzoyl chloride, isophthaloyl chloride, dibutyl phosphate, 3-chloropropionic acid or methyl tosylate may be added during the preparation.
• the reaction temperature in the preparation of the prepolymers A) is preferably 20 to 120 ° C and more preferably 60 to 100 ° C.
• the prepolymers produced have a measured according to DIN EN ISO 11909 average NCO content of 2 to 10 wt .-%, preferably 2.5 to 8 wt .-%.
• the prepolymers A) can have an average NCO functionality of from 1.5 to 2.5, preferably from 1.6 to 2.4, more preferably from 1.7 to 2.3, very particularly preferably from 1.8 to 2.2 and in particular from 2.
• the organic fillers of component C) may preferably be hydroxy-functional compounds, in particular polyether polyols having repeating ethylene oxide units.
• the fillers of component C) have an average OH functionality of from 1.5 to 3, preferably from 1.8 to 2.2 and particularly preferably from 2.
• liquid polyethylene glycols such as PEG 200 to PEG 600
• their mono- or dialkyl ethers such as PEG 500 dimethyl ether
• liquid polyether and polyester polyols liquid polyesters
• Ultramoll (Lanxess AG, Leverkusen, DE) as well as glycerin and its liquid derivatives, e.g. Triacetin (Lanxess AG, Leverkusen, DE) are used.
• the viscosity of the organic fillers measured according to DIN 53019 at 23 ° C. is preferably 50 to 4000 mPas, more preferably 50 to 2000 mPas.
• polyethylene glycols are used as organic fillers. These preferably have a number average molecular weight of 100 to 1000 g / mol, more preferably 200 to 400 g / mol.
• component E) is a tertiary amine of the general formula (IV) contains, in the R 4 , R 5 , R 6 may independently be alkyl or heteroalkyl radicals with heteroatoms in the alkyl chain or at the end thereof, or R 4 and R 5 together with the nitrogen atom bearing them may form an aliphatic, unsaturated or aromatic heterocycle, optionally may contain other heteroatoms.
• polyurea systems are characterized by a particularly rapid curing.
• the compounds used in component E) may very particularly preferably be tertiary amines selected from the group triethanolamine, tetrakis (2-hydroxyethyl) ethylenediamine, N, N-dimethyl-2- (4-methylpiperazin-1-yl) ethanamine, 2 - ⁇ [2- (dimethylamino) ethyl] (methyl) amino ⁇ ethanol, 3,3 ', 3 "- (1,3,5-triazinan-1,3,5-triyl) tris (N, N-dimethyl-propan-1-amine).
• tertiary amines selected from the group triethanolamine, tetrakis (2-hydroxyethyl) ethylenediamine, N, N-dimethyl-2- (4-methylpiperazin-1-yl) ethanamine, 2 - ⁇ [2- (dimethylamino) ethyl] (methyl) amino ⁇ ethanol, 3,3 ', 3 "- (1,3,5-triazin
• component E) contains from 0.2 to 90% by weight of water and / or from 0.1 to 1.0% by weight of the tertiary amine, based in each case on the polyurea system ,
• the polyurea system preferably contains 10 to 90 wt .-% of water, based on the polyurea system.
• component E) contains 0.2 to 2.0% by weight of water, based on the polyurea system.
• pharmacologically active agents such as analgesics with and without anti-inflammatory action, anti-inflammatory drugs, antimicrobial active substances, antimycotics, antiparasitic acting substances or combinations thereof may also be incorporated in the polyurea systems.
• the active compounds may be in the form of a pure active ingredient or else in encapsulated form in order, for example, to achieve a time-delayed release.
• a large number of types and classes of active substances can be used as medicinal agents.
• Such a medicinal agent may comprise, for example, a nitric oxide-releasing component, preferably L-arginine or an L-arginine-containing or L-arginine-releasing component, more preferably L-arginine hydrochloride, in vivo conditions.
• a nitric oxide-releasing component preferably L-arginine or an L-arginine-containing or L-arginine-releasing component, more preferably L-arginine hydrochloride
• proline, ornithine and / or other biogenic intermediates such as biogenic polyamines (spermine, spermitine, putrescine or bioactive artificial polyamines) can be used.
• biogenic polyamines spermine, spermitine, putrescine or bioactive artificial polyamines
• Further active compounds which can be used according to the invention comprise at least one substance selected from the group of vitamins or provitamins, carotenoids, analgesics, antiseptics, hemostyptics, antihistamines, antimicrobial metals or their salts, herbal wound healing substances or mixtures of substances, plant extracts, enzymes, growth factors, enzyme inhibitors and combinations thereof.
• Non-steroidal analgesics especially salicylic acid, acetylsalicylic acid and its derivatives, e.g. Aspirin®, aniline and its derivatives, acetaminophen e.g. Paracetamol®, antranilic acid and its derivatives e.g. Mefenamic acid, pyrazole or its derivatives e.g. Methamizole, Novalgin®, phenazone, antipyrine®, isopropylphenazone and most preferably arylacetic acids and their derivatives, heteroarylacetic acids and their derivatives, arylpropionic acids and their derivatives and herteroarylpropionic acids and their derivatives, e.g. Indometacin®, Diclophenac®, Ibuprofen®, Naxoprophen®, Indomethacin®, Ketoprofen®, Piroxicam®.
• salicylic acid e.g. Aspirin®, aniline and its derivatives, ace
• Growth factors include aFGF (Acidic Fibroplast Growth Factor), EGF (Epidermal Growth Factor), PDGF (Platelet Derived Growth Factor), rhPDGF-BB (becaplermin), PDECGF (Platelet Derived Endothelial Cell Growth Factor), bFGF ( Basic Fibroplast Growth Factor), TGF ⁇ ; (Transforming Growth Factor alpha), TGF (Transforming Growth Factor beta), KGF (Keratinocyte Growth Factor), IGF1 / IGF2 (Insulin-Like Growth Factor) and TNF (Tumor Necrosis Factor).
• Vitamins or provitamins in particular are the fat-soluble or water-soluble vitamins vitamin A, group of retinoids, provitamin A, group of carotenoids, in particular ⁇ -carotene, vitamin E, group of tocopherols, in particular ⁇ tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -Tocopherol and ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol and ⁇ -tocotrienol, vitamin K, phylloquinone, in particular phytomenadione or vegetable vitamin K, vitamin C, L-ascorbic acid, vitamin B1, thiamine, vitamin B2, riboflavin, vitamin G, Vitamin B3, niacin, nicotinic acid and nicotinamide, vitamin B5, pantothenic acid, provitamin B5, panthenol or dexpanthenol, vitamin B6, vitamin B7, vitamin H, biotin, vitamin B
• an antiseptic use must be made of such a composition that acts as a stain, a bactericide, a bacteriostatic agent, a fungicide, a virucidal agent, a virustatic agent and / or a general microbiocidal agent.
• antimicrobial metals are to be used in particular as antiseptics.
• antimicrobial metals Silver, copper or zinc and their salts, oxides or complexes in combination or used alone.
• extracts of chamomile, witch hazel extracts are used as herbal, wound healing promoting agents.
• the content of the active ingredients depends primarily on the medically required dose and also on the compatibility with the other constituents of the composition according to the invention.
• the polyurea system according to the invention is particularly suitable for sealing, bonding, bonding or covering of cell tissue and in particular for producing an adhesion barrier and / or for stopping the escape of blood or tissue fluids or for closing leaks in cell tissue.
• it can be used for the use or for the production of an agent for sealing, bonding, gluing or covering of human or animal cell tissue.
• fast-curing, strongly adhering to the tissue, transparent, flexible and biocompatible adhesive seams can be produced.
• it can be used to create fast-curing adhesion barriers that are "tack-free" after a short time and partially break down within a few days or weeks postoperatively.
• Yet another object of the invention is metering system with two chambers for a polyurea system according to the invention for producing an adhesion barrier, wherein in one chamber the component A) a first subset of E) and in the other chamber, the components B) and optionally the components C), D) and a second subset of E) of the polyurea system are included.
• a metering system is particularly suitable for applying the polyurea system as an adhesion barrier to tissue.
• the component E) preferably contains 10 to 90 wt .-% water, based on the polyurea system.
• the components A) and B) are present in mutually equivalent amounts of substance and the first and second subset of E) are each selected such that the volume of A) and first Subset of E) is largely identical to the volume of B), the second subset of E) and the optional components C) and D).
• Such a division is advantageous because then with the dosing with the same volume flows from the two chambers a hydrogel can be deployed, which sets in a short time and thereby forms a reliable acting adhesion barrier.
• the present invention relates to a metering system with two chambers for a polyurea system according to the invention for use as a tissue adhesive, wherein in one chamber the component A) and in the other chamber the components B) and optionally the components C), D) and E ) of the polyurea system are included.
• a metering system is particularly suitable for applying the polyurea system as a tissue adhesive to tissue.
• the component E) preferably contains 0.2 to 2.0 wt .-% water, based on the polyurea system.
• the molecular weights were determined by gel permeation chromatography (GPC) as follows: The calibration was carried out with polystyrene standards having molecular weights of Mp 1,000,000 to 162. The eluent was tetrahydrofuran p.A. used. The following parameters were observed during the double measurement: Degassing: Online - Degasser; Flow: 1 ml / min, analysis time: 45 minutes; Detectors: refractometer and UV detector; Injection volume: 100 ⁇ l - 200 ⁇ l. The calculation of the molecular weight averages Mw; Mn and Mp and the polydispersity Mw / Mn were software-based. Baseline points and evaluation limits were determined in accordance with DIN 55672 Part 1.
• the NCO content was determined volumetrically in accordance with DIN-EN ISO 11909.
• the viscosity was determined according to ISO 3219 at 23 ° C.
• the determination of the residual monomer content was carried out according to DIN ISO 17025.
• the NMR used was a Bruker DRX 700 instrument.
• the primary diamine is placed under a nitrogen atmosphere and the diethyl acrylate is added dropwise with stirring, so that the reaction temperature of 30 ° C is not exceeded. After the exotherm has subsided, it is heated to 60 ° C. for 12 hours.
• PA 336 g of HDI were initially charged with 0.1% by weight of benzoyl chloride and heated to 80 ° C. Then 197.7 g of the previously prepared polyester A) were metered in with stirring over 1 h and stirred until reaching a constant NCO content at 80 ° C on. The excess HDI was removed by means of a thin-film evaporator at 140 ° C. and 0.13 mbar. The prepolymer obtained had an NCO content of 5.8% (equivalent weight: 724.14 g / mol) and a viscosity of 1010 mPas / 23 ° C. The residual monomer content was ⁇ 0.03% HDI.
• a cylindrical piece of gel about 5 cm high and 0.6 cm in diameter is stored at 37 ° C in PBS saline buffer solution (pH 7.4, Aldrich P-5368) in a shaking incubator and checked daily if the specimen has dissolved , A sample is considered mined if no solid is left.
• PBS saline buffer solution pH 7.4, Aldrich P-5368
• the results of the degradation experiments under simulated conditions prove that the polyurea hydrogels prepared with the beta-amino acid ester according to the invention degrade within the body in a short time.
• the degradation rate of the hydrogel can be adjusted by selecting the components reacted with one another to form the polyurea.

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• 2012
  • 2012-01-09 EP EP12150420.3A patent/EP2612846A1/fr not_active Ceased
• 2013
  • 2013-01-04 WO PCT/EP2013/050083 patent/WO2013104564A1/fr active Application Filing

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